EP2311447B1 - Therapeutic or prophylactic agent for diabetes, obesity, dyslipidemia or metabolic syndrome comprising benzylamine derivative or pharmaceutically acceptable acid addition salt thereof - Google Patents

Therapeutic or prophylactic agent for diabetes, obesity, dyslipidemia or metabolic syndrome comprising benzylamine derivative or pharmaceutically acceptable acid addition salt thereof Download PDF

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EP2311447B1
EP2311447B1 EP09803036A EP09803036A EP2311447B1 EP 2311447 B1 EP2311447 B1 EP 2311447B1 EP 09803036 A EP09803036 A EP 09803036A EP 09803036 A EP09803036 A EP 09803036A EP 2311447 B1 EP2311447 B1 EP 2311447B1
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diabetes
obesity
therapeutic
prophylactic agent
dyslipidemia
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French (fr)
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EP2311447A1 (en
EP2311447A4 (en
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Ko Hasebe
Satoru Yoshikawa
Hideki Kozono
Seiji Okazaki
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Toray Industries Inc
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Toray Industries Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a therapeutic or prophylactic agent to diabetes, obesity, dyslipidemia or metabolic syndrome, which comprises a benzylamine derivative represented by formula (I) or a pharmaceutically acceptable acid addition salt thereof, as defined in the claims.
  • Diabetes is a chronic disease caused by dysbolism leading to chronic hyperglycemic state by insufficient action of insulin.
  • Diabetes is grouped into type 1 diabetes characterized by insufficient secretion of insulin and type 2 diabetes characterized by lowered secretion of insulin and lowered sensitivity (insulin resistance).
  • type 2 diabetes which accounts for 90 to 95% of diagnosed diabetes, is said to be closely correlated with the life-style diseases that worry men of today, such as obesity, hypertension, hyperlipemia and metabolic syndrome.
  • Nonpatent Literature 1 sulfonylureas, phenylalanine derivatives, ⁇ -glucosidase inhibitors, biguanides, thiazolidine derivatives and the like, but use of these drugs is restricted, because of accompanied adverse reaction such as severe hypoglycemia, gastrointestinal tract disorder, liver function disorder or lactic acidosis.
  • sulfonylureas and thiazoline derivatives are known to accelerate increase of body weight (Nonpatent Literature 1).
  • Obesity which is in the state where energy is stored abnormally in adipose tissue by overeating and lack of exercise, can cause type 2 diabetes and also hypertension, heart disease and others.
  • Anti-obesity drugs include Mazindol, Orlistat, Rimonabant and the like.
  • Mazindol has primary pharmacologic actions of central suppression of feeding and acceleration of heat production in peripheral organs, but is often accompanied with central adverse reactions such as nausea, headache and dizziness, and thus, strict control is needed for its use.
  • Orlistat suppresses fat absorption and thus leads to decrease of body weight by inhibiting lipases, but it also inhibits absorption of lipophillic vitamins, and thus, vitamins should be supplemented, as needed.
  • Rimonabant suppresses appetite and leads to decrease of body weight by interaction with cannabinoid 1 receptor, but has a problem of central adverse reactions such as dizziness, nausea and headache.
  • Nonpatent Literatures 2 to 4 These anti-obesity drugs have not only action to reduce body weight but also various disadvantages and adverse reactions, and for that reason, there exists a need for development of an anti-obesity drug that is more effective and superior in efficiency in use.
  • Dyslipidemia is a disease accompanied with abnormality in blood cholesterol and triglyceride levels. Dyslipidemia results in arteriosclerosis, further leading to increase of the risks of coronary disease such as angina cordis and myocardial infarction.
  • Anti-dyslipidemia drugs are drugs for reduction of the blood triglyceride and LDL cholesterol levels that are important for prevention of coronary diseases (Nonpatent Literature 5).
  • Anti-dyslipidemia drugs include statins (HMG-CoA reductase inhibitor) such as pravastatin and atrovastatin; bile acid absorbents such as cholestyramine and cholestimide; fibrates such as clofibrate and bezafibrate; and the like.
  • Statins occasionally cause adverse reactions such as digestive organ symptoms and rhabdomyolysis.
  • Bile acid absorbents have adverse reactions such as constipation and abdominal bloating and occasionally inhibit absorption of drugs used in combination. Fibrates should be used carefully with caution to the adverse reactions such as rhabdomyolysis and liver function disorder. All of these anti-dyslipidemia drugs have action to decrease serum triglyceride or cholesterol level, but, in fact, they also have various disadvantages and adverse reactions (Nonpatent Literature 2).
  • Metabolic syndrome is a syndrome in combination of some of abdominal obesity, hypertriglyceridemia, hypo-HDL-cholestrolemia, hyperglycemia and hypertension, and it is considered to be a syndrome higher in the risk of arteriosclerotic diseases, because these symptoms in combination leads to increase of the risk of arteriosclerotic diseases.
  • NCEP National Cholesterol Education Program
  • the International Diabetes Federation (hereinafter, IDF) and the Examination Committee of Criteria for Obesity Disease in Japan define, as the metabolic syndrome, a syndrome showing abdominal obesity as essential item and additionally multiple items selected from hypertriglyceridemia, hypo-HDL-cholesterolemia, hypertension and hyperglycemia.
  • Nonpatent Literatures 8 and 9 ⁇ 3 adrenoreceptor agonists are proposed as a new drug candidate to type 2 diabetes and obesity (Nonpatent Literatures 8 and 9).
  • the ⁇ 3 adrenoreceptors which are present in the fat cells of rodents and human, are suggested to have an important role in regulation of fat decomposition and heat production (Nonpatent Literatures 10 and 11).
  • Functional deterioration of ⁇ 3 adrenoreceptor results, for example, in accumulation of body fat and thus, its correlation with development of obesity is suggested (Nonpatent Literature 12).
  • development of a ⁇ 3 adrenoreceptor agonist as diabetes drug is so far unfruitful, because of the adverse reactions on the cardiovascular system.
  • Patent Document 1 discloses a ⁇ 3 adrenoreceptor agonist (amine derivative). However, there is no disclosed pharmacological data showing the efficacy thereof to diabetes and obesity.
  • Nonpatent Literature 8 discloses the following benzylamine derivative (1) as a ⁇ 3 adrenoreceptor agonist.
  • the data available concerning the efficacy thereof to diabetes and obesity is only limited to the action of decomposing free fatty acids.
  • Nonpatent Literatures 8 and 13 No drug is developed from the benzylamine derivative (1) above and analogous benzylamine derivatives, which are ⁇ 3 adrenoreceptor agonists, because there are adverse reactions on the cardiovascular system (prolongation of QT interval and increase of heart rate) (Nonpatent Literatures 8 and 13).
  • Patent Document 2 discloses a wide range of compounds including part of the benzylamine derivatives (1) above. However, usefulness of these compounds to diabetes, obesity, dyslipidemia or metabolic syndrome is currently unknown.
  • an object of the present invention is to provide a therapeutic or prophylactic agent for diabetes, obesity, dyslipidemia or metabolic syndrome, which can exhibit significant efficacy at lower dose and does not have an increase of heart rate or a prolongation of QT interval which is an adverse side effect on the cardiovascular system.
  • KK/Ay mice type 2 diabetes model mice
  • DIO mice Diet Induced Obesity mice: hereinafter, referred to as DIO mice
  • a new benzylamine derivative superior in selectivity to ⁇ 3 adrenoreceptor has a favorable efficacy to diabetes, obesity, dyslipidemia or metabolic syndrome, but does not have the adverse reactions on the cardiovascular system (prolongation of QT interval and increase of heart rate), which is a serious problem associated with chemical therapy of chronic diseases, and made the present invention.
  • the present invention provides a therapeutic or prophylactic agent to diabetes, obesity, dyslipidemia or metabolic syndrome, which comprises a benzylamine derivative represented by General Formula (I) wherein, R 1 represents an alkyl group having 1 to 6 carbon atoms; R 2 represents an alkyl group having 1 to 6 carbon atoms; R 3 and R 5 each independently represent a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms; and R 4 represents a hydrogen atom or an alkoxy group having 1 to 6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.
  • R 1 represents an alkyl group having 1 to 6 carbon atoms
  • R 2 represents an alkyl group having 1 to 6 carbon atoms
  • R 3 and R 5 each independently represent a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to
  • R 1 is preferably methyl, ethyl, propyl, isopropyl or tert-butyl;
  • R 2 is preferably methyl, ethyl, propyl or isopropyl;
  • R 3 and R 5 are each independently preferably methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy or chloro; and
  • R 4 is preferably a hydrogen atom, methoxy, ethoxy, propoxy or isopropoxy.
  • R 2 is methyl;
  • R 3 and R 5 are each independently methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy or chloro; and
  • R 4 is a hydrogen atom, methoxy, ethoxy, propoxy or isopropoxy, and more preferably, R 1 and R are methyl; R 3 and R 5 are each independently methyl, trifluoromethyl, methoxy or chloro; and R 4 is a hydrogen atom or methoxy.
  • R 1 and R 2 are methyl; R 3 and R 5 are simultaneously methyl, trifluoromethyl, methoxy or chloro; and R 4 is a hydrogen atom.
  • the present invention provides use of a benzylamine derivative represented by General Formula (I) above or a pharmaceutically acceptable acid addition salt thereof in production of a pharmaceutical for treatment or prevention of diabetes, obesity, dyslipidemia or metabolic syndrome.
  • the therapeutic or prophylactic agent according to the present invention shows distinctive therapeutic or preventive effect to diabetes, obesity, dyslipidemia or metabolic syndrome without adverse reactions to the cardiovascular system such as increase of heart rate and prolongation of QT interval.
  • alkyl means a monovalent linear or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms.
  • alkoxy group means an -OR group, in which R is the alkyl as defined herein.
  • halogen means fluoro, chloro, bromo or iodo.
  • haloalkyl means an alkyl as defined herein of which hydrogen atoms are replaced with the one or more halogen atoms as defined herein at an arbitrary position.
  • diabetes means a disease diagnosed as diabetes according to the diagnostic standard, for example, of WHO (World Health Organization), Japan Diabetes Society, American Diabetes Association or European Association for the Study of Diabetes and includes type 1 diabetes, type 2 diabetes and pregnancy diabetes.
  • the type 2 diabetes is characterized by its resistance to the action of insulin, i.e., "insulin resistance”.
  • the "insulin resistance” means a disease diagnosed as insulin resistance, based on the insulin resistance index (fasting blood sugar (mg/dL) ⁇ fasting insulin ( ⁇ U/mL) ⁇ 405) or on the results obtained by examination by glucose clamp method or the like and includes syndrome X additionally.
  • diseases with "insulin resistance” include fatty liver, particularly NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis), coronary heart diseases (CHDs), arteriosclerotic diseases, hyperglycemia, lipodosis, impaired glucose tolerance, hypertension, hyperlipemia, diabetes complications, pregnancy diabetes and polycystic ovary syndrome.
  • dyslipidemia means a disease diagnosed as dyslipidemia according to the diagnostic standard, for example, of WHO or Japan Atherosclerosis Society and includes hyperlipemia, hypercholestrolemia, hyper-LDL-cholestrolemia, hypo-HDL-cholestrolemia and hypertriglyceridemia.
  • obesity means a disease diagnosed as obesity according to the diagnostic standard, for example, of WHO or Japan Society for the Study of Obesity and includes "overweight”.
  • metabolic syndrome means a disease diagnosed as metabolic syndrome according to the diagnostic standard, for example, of WHO, NCEP, IDF or the Committee for Diagnostic Standard of Metabolic Syndrome in Japan Atherosclerosis Society.
  • therapeutic or prophylactic agent includes an agent used for treatment or prevention and also an agent used both for treatment and prevention simultaneously.
  • the therapeutic or prophylactic agent for diabetes, obesity, dyslipidemia or metabolic syndrome of the present invention is characterized by containing a benzylamine derivative represented by General Formula (I): wherein, R 1 represents an alkyl group having 1 to 6 carbon atoms; R 2 represents an alkyl group having 1 to 6 carbon atoms; R 3 and R 5 each independently represent a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms; and R 4 represents a hydrogen atom or an alkoxy group having 1 to 6 carbon atoms or a pharmaceutically acceptable acid addition salt thereof.
  • R 1 represents an alkyl group having 1 to 6 carbon atoms
  • R 2 represents an alkyl group having 1 to 6 carbon atoms
  • R 3 and R 5 each independently represent a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group
  • examples of the alkyl groups having 1 to 6 carbon atoms of R 1 , R 2 , R 3 and R 5 include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, and hexyl.
  • haloalkyl groups having 1 to 6 carbon atoms of R 3 and R 5 include, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl and 2,2,2-trichloroethyl.
  • alkoxy groups having 1 to 6 carbon atoms of R 3 , R 4 and R 5 include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
  • halogen atoms of R 3 and R 5 include chloro, bromo and iodo.
  • R 1 is preferably methyl, ethyl, propyl, isopropyl or tert-butyl, more preferably methyl or isopropyl, and still more preferably methyl.
  • R 2 is preferably methyl, ethyl, propyl or isopropyl, more preferably, methyl, ethyl or propyl, and still more preferably methyl.
  • R 3 and R 5 are each independently, preferably methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy or chloro, more preferably methyl, trifluoromethyl, methoxy or chloro, and R 3 and R 5 are still more preferably simultaneously methyl, trifluoromethyl, methoxy or chloro.
  • R 4 is preferably a hydrogen atom, methoxy, ethoxy, propoxy or isopropoxy, more preferably a hydrogen atom, methoxy or ethoxy, and still more preferably a hydrogen atom or methoxy.
  • the benzylamine derivative represented by General Formula (I) has two asymmetrical carbon atoms, so that optical isomers and diastereomers which are based thereon exist.
  • the present invention also includes these single isomers or a racemate or diastereomer mixture thereof.
  • Examples of the pharmaceutically acceptable acid addition salts of the benzylamine derivative represented by General Formula (I) include inorganic acid salts such as hydrochloric acid salt, sulfuric acid salt, nitric acid salt, hydrobromic acid salt, hydroiodic acid salt and phosphoric acid salt; organic carboxylic acid salts such as acetic acid salt, lactic acid salt, citric acid salt, oxalic acid salt, glutaric acid salt, malic acid salt, tartaric acid salt, fumaric acid salt, mandelic acid salt, maleic acid salt, benzoic acid salt and phthalic acid salt; organic sulfonic acid salts such as methanesulfonic acid salt, ethanesulfonic acid salt, benzenesulfonic acid salt, p-toluenesulfonic acid salt and camphorsulfonic acid salt.
  • inorganic acid salts such as hydrochloric acid salt, sulfuric acid salt, nitric acid salt, hydrobromic acid salt, hydro
  • hydrochloric acid salt More favorable among them are hydrochloric acid salt, hydrobromic acid salt, phosphoric acid salt, tartaric acid salt and methanesulfonic acid salt; and still more favorable are hydrochloric acid salt, tartaric acid salt and methanesulfonic acid salt.
  • the benzylamine derivatives of the present invention can be produced by a method suitable to the characteristics thereof such as the basic skeleton and the kinds of the substituent groups.
  • the starting materials and reagents used for production of these compounds are generally commercially available or can be synthesized by a procedure known by those who are skilled in the art, according to a method described in reference literature such as Peter et al., "Organic Reaction", Wiley & Sons or Fieser, "Fieser and Fieser's Reagent for Organic synthesis", Wiley & Sons and the like.
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as those defined above.
  • benzylamine derivative represented by General Formula (I) can be obtained using a method known to those who are skilled in the art, for example, by reductive alkylation of an amine derivative represented by General Formula (II) with a benzaldehyde derivative represented by General Formula (III).
  • the solvents that may be used include aprotic polar solvents such as dimethylformamide (DMF), dimethylacetamide and dimethylsulfoxide (DMSO); ether solvents such as diethylether, tetrahydrofuran (THF), dimethoxyethane (DME) and dioxane; hydrocarbon solvents such as benzene, toluene and xylene; halogenated solvents such as dichloromethane, chloroform and 1,2-dichloroethane; alcoholic solvents such as methanol, ethanol and propanol; or the mixed solvents thereof. Normally, use of an alcoholic solvent such as methanol or ethanol, in particular methanol, gives favorable results.
  • the benzaldehyde derivative (III) can be used in an amount of 0.5 to 20 equivalents to the amine derivative (II), but the ratio used normally, 0.5 to 10 equivalents, preferably 0.5 to 3 equivalents.
  • the reducing agents that may be used include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane-pyridine complex and the like, and, in particular, sodium cyanoborohydride and borane-pyridine complex are used favorably.
  • the reducing agent can be used in an amount of 0.5 to 50 equivalents to the amine derivative (II), but the ratio used is normally, 1 to 20 equivalents, preferably 1 to 10 equivalents.
  • a reaction temperature normally of -40 to 150°C, preferably of -30 to 80°C, gives satisfactory results.
  • the reaction time is selected properly according to the conditions such as reaction temperature, but normally a reaction time of 30 minutes to 10 hours gives satisfactory results.
  • the concentration of the amine derivative (II) in the reaction mixture is not particularly limited, but normally, preferably 0.001 to 1 mol/L.
  • the solvents that may be used include halogenated solvents such as dichloromethane, chloroform and 1, 2-dichloroethane; alcoholic solvents such as methanol, ethanol and propanol; ether solvents such as dioxane and diethylether, or the mixed solvents thereof. Normally, use of an alcoholic or ether solvent, in particular methanol, propanol or dioxane, gives favorable results.
  • the amount of the acid added is not particularly limited, but the ratio is within the range of 1 to 30 equivalents with respect to the benzylamine derivative (I), and normally, a ratio of 1 to 10 equivalents, preferably 1 to 5 equivalents, gives satisfactory results.
  • the amine derivative represented by General Formula (II), which is used as the starting material in Scheme 1, can be obtained for example, by debenzylation which is a method known to those who are skilled in the art of the amine represented by General Formula (IV), which can be synthesized by the method described in WO 2005/040093 , as shown in Scheme 2.
  • the debenzylation is generally carried out by hydrogenolysis in the presence of a metal catalyst.
  • R 1 and R 2 are the same as those defined above, and Bn represents a benzyl group.
  • an alcoholic solvent such as methanol, ethanol or propanol
  • an ether solvent such as tetrahydrofuran (THF), dimethoxyethane (DME) or dioxane
  • THF tetrahydrofuran
  • DME dimethoxyethane
  • dioxane a mixture with an alcoholic solvent such as methanol or ethanol gives favorable results.
  • Catalysts commonly used in hydrogenation reaction such as platinum oxide, palladium hydroxide and palladium-carbon, can be used as the metal catalysts above, but palladium hydroxide and palladium-carbon are used favorably.
  • the metal catalyst can be used in an amount of 0.001 to 50 equivalents with respect to the amine (IV), but the ratio used is normally 0.05 to 20 equivalents, preferably 0.1 to 5 equivalents.
  • the reaction can be carried out at a reaction temperature of -30 to 80°C, preferably 10 to 50°C, and at a hydrogen pressure of 1 to 100 atmospheres, preferably 1 to 30 atmospheres, but normally, combination of room temperature and normal pressure gives favorable results.
  • the reaction time is selected properly according to the reaction condition, but normally, a reaction time of 30 minutes to 48 hours gives favorable results.
  • the concentration of the substrate (IV) in the reaction mixture is not particularly limited, but normally, preferably 0.001 to 1 mol/L.
  • the efficacy of treatment to diabetes, obesity, dyslipidemia or metabolic syndrome with the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt can be determined by using normal and disease-model animals, such as mice, rats, dogs, and monkeys, (for example, diabetes/obesity model animals described in Takeuchi et al., "Folia Pharmacologica Japonica", 2006, 128, p.37-41 and diabetes/obesity mice described in Winzell M.S. et al., Diabetes, 2004, 53, p. S215-S219 ).
  • Efficacy in treatment of diabetes with the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt can be determined, for example, based on clinical symptoms (e.g., blood sugar or plasma glucose concentration), diabetes-related test results (e.g., blood glycated Hemoglobin A1c: HbA1C) or blood sugar in oral glucose tolerance test (OGTT) after two hours.
  • clinical symptoms e.g., blood sugar or plasma glucose concentration
  • diabetes-related test results e.g., blood glycated Hemoglobin A1c: HbA1C
  • OGTT oral glucose tolerance test
  • the blood sugar and the plasma glucose concentration can be determined by using a simple blood sugar analyzer, which determines blood sugar, by using a reaction of glucose oxidase, based on the principle of detecting absorbance in colorimetric method or quantitative electrochemical determination (glucose sensor method).
  • Efficacy of the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt in treatment to the diseases with "insulin resistance” can be determined by using, as indicator, the glucose utilization rate or the glucose injection rate of individuals when insulin is injected in glucose clamp test.
  • Insulin tolerance test ITT is generally used as a simple and convenient method of evaluating the insulin resistance state of individuals, and specifically, insulin sensitivity is evaluated by using the change in blood sugar under insulin load as an indicator ( Tanaka et al., Proc. Natl. Acad. Sci, 2003, 100, P.15924-15929 ).
  • Efficacy of the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt in treatment of dyslipidemia can be evaluated by using the plasma triglyceride level of individuals as an indicator.
  • those with the compound administered are likely have advantage of reduced blood triglycerides.
  • Triglycerides can be determined by using a measurement kit of colorimetric method by using a commercially available enzyme reaction.
  • Efficacy of the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt in treatment of obesity can be evaluated by using the body weight, abdominal circumference, body mass index (BMI) or internal fat level of individuals as an indicator.
  • BMI body mass index
  • those with the compound administered are likely lower in the body weight, abdominal circumference, body mass index (BMI) or internal fat level of the individuals.
  • the drug containing the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt is effective not only to human, but also to mammals other than human, such as mouse, rat, hamster, rabbit, cat, dog, bovine, sheep and monkey.
  • the drug may be the free base or the acid addition salt itself or a mixture thereof with suitable additives such as diluents, stabilizers, preservatives, buffers, solubilizing agents, emulsifiers, diluent and isotonic agents.
  • suitable additives such as diluents, stabilizers, preservatives, buffers, solubilizing agents, emulsifiers, diluent and isotonic agents.
  • suitable additives such as diluents, stabilizers, preservatives, buffers, solubilizing agents, emulsifiers, diluent and isotonic agents.
  • suitable additives such as diluents, stabilizers, preservatives, buffers, solubilizing agents, emulsifiers, diluent and isotonic agents.
  • the administration forms include oral preparations such as tablets, capsules, granules, powders, and syrups; parenteral preparation
  • the therapeutic or prophylactic agent for diabetes, obesity, dyslipidemia or metabolic syndrome according to the invention desirably contains the active ingredient in an amount of 0.00001 to 90 wt %, more preferably 0.0001 to 70 wt %.
  • the amount thereof is selected properly according to the symptom, age, body weight and administration method, but the therapeutic or prophylactic agent can be administered to an adult as the active ingredient in an amount of 0.1 ⁇ g to 1 g per day in the case of injection, 1 ⁇ g to 10 g in the case of oral preparation, and 1 ⁇ g to 10 g in the case of patch, and it can be administered all at once or several times in portions a day.
  • the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt can be used in combination with other diabetes drugs, drugs for treatment of diseases with "insulin resistance", anti-obesity drugs, anti-dyslipidemia drugs, and metabolic syndrome drugs (hereinafter, referred to as combination drugs).
  • the time of administration of the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt and the combination drug is not particularly limited, and these drugs may be administered to a patient simultaneously or separately with time difference.
  • the amount of the combination drug administered can be selected properly according to the application clinically used.
  • the blending ratio of the benzylamine derivative represented by General Formula (I) or the pharmaceutically acceptable acid addition salt to the combination drug can be selected properly according to the patient to be administered, administration route, symptom, combination and others.
  • the combination drugs used include insulin preparations (ultrafast-acting insulin preparations, fast-acting insulin preparations, mixed insulin preparations, intermediate insulin preparations, long-acting insulin preparations, long-acting soluble insulin preparation, transpulmonary insulin preparation, oral insulin preparation, etc.), insulin resistance-improving drugs (pioglitazone, rosiglitazone, netoglitazon, farglitazar, rivoglitazone, balaglitazone, etc.), ⁇ -glucosidase inhibitors (acarbose, voglibose, miglitol, emiglitate, etc.), biguanides (metformin, buformin, etc.), sulfonyl ureas (tolbutamide, acetohexamide, chlorpropamide, tolazamide, glyclopyramide, glybuzole, glibenclamide, gliclazide, glimepiride, glipizide, gliquid insulin preparation
  • Alpha Screen cAMP Detection Kit (6760625, Perkin Elmer), which uses the change of cAMP production as indicator, was used for evaluation of the agonistic activity in all cases.
  • Various cells were cultured in culture flasks, and the cells were separated and collected by EDTA/PBS treatment on the test day and diluted with a stimulus buffer (0.1% BSA, 500 ⁇ M IBMX, 5 mM HEPES, HBSS, pH 7.4) to a cell concentration of 10,000 cells/well.
  • a stimulus buffer (0.1% BSA, 500 ⁇ M IBMX, 5 mM HEPES, HBSS, pH 7.4
  • Standard solution cAMP
  • a compound solution of Example was added onto a 384-well plate (Optiplate New, #6007290, Perkin Elmer) in an amount of 5 ⁇ L to the final concentration (10 -10 to 10 -4 M) and then, 5 ⁇ L of anti-cAMP acceptor beads or a cell/Anti-cAMP acceptor beads mixture solution was added thereto, and the mixture was allowed to react at 37°C in a dark place for 30 minutes.
  • biotinylated-cAMP/streptavidin donor beads prepared in a lysis buffer (0.1% BSA, 0.3% Tween-20, 5 mM HEPES, pH 7.4) were added in an amount of 15 ⁇ L, and the mixture was allowed to react at room temperature in a dark place for 60 minutes, and the AlphaScreen signals (cps) from the mixture was determined with Fusion ⁇ (Packard BioScience).
  • the reaction rate of the compound of each Example was first calculated, based on 100% of the maximum amount of cAMP produced by isoproterenol, and pEC50 value (negative common logarithm of 50% reaction concentration towards isoproterenol) was calculated by linear regression.
  • Examples 1 to 5 were all superior in selectivity to ⁇ 3 adrenoreceptor and were considered to have similar properties.
  • KK/Ay male mice of 5 weeks of age (CLEA Japan, Inc.) were purchased; a feeding stuff for growth CMF (Oriental Yeast) was provided since the day of arrival; and mice after growth for 3 weeks or longer were used.
  • the compound of Example 1 was diluted to 2 mg/mL, as it is dissolved in physiological saline, and the solution was administered subcutaneously in an amount of 5 mL/kg, by using a disposable syringe (Terumo) and a 26G injection needle (Terumo).
  • Physiological saline was administered to the mice in the vehicle group.
  • the solution was administered once a day from the day of first administration (day 0) to day 13, and the tail vein was cut open with a knife (disposable scalpel, FEATHER) and the blood sugar was determined with a simplified blood sugar analyzer (MediSense Precision Xceed, Abotto Japan).
  • Statistical treatment of the individual data obtained was carried out by a two-group test (unpaired t-test).
  • Example 1 lowered the blood sugar statistically significantly, compared to the solvent group (Table 4). The result indicates that the compound of Example 1 is effective to type 2 diabetes.
  • the compound of Example 1 was diluted to 2 mg/mL or 0.6 mg/mL, as it is dissolved in physiological saline, and the solution was administered subcutaneously in an amount of 5 mL/kg, by using a disposable syringe (Terumo) and a 26G injection needle (Terumo).
  • Physiological saline was administered in the vehicle group.
  • the solution was administered once a day from the day of first administration (day 0) to day 26.
  • the body weight was determined on day 26; the tail vein was cut open with a knife (disposable scalpel, FEATHER); and the blood sugar was determined with a simplified blood sugar analyzer (MediSense Precision Xceed, Abotto Japan).
  • the blood was collected (approximately 70 ⁇ L) from the same site by using a heparin-treated capillary (Hematokrit Kapilaren, 75 ⁇ L, HIRSCMANN LABORGERATE) and the collected blood was centrifuged (12,000 rpm, 7 min, 4°C) in a hematocrit centrifuge (KUBOTA3100, Kubota Corp.) and the plasma was stored, as it is frozen in an Eppendorf tube, until it is used for measurement of triglyceride.
  • the triglyceride measurement was carried out by using Triglyceride E-Test Wako (Wako Pure Chemical Industries).
  • the mouse was left non-feeded in a fasting cage after drug administration on day 26.
  • the fasting blood sugar was determined by a method identical with that used for blood sugar measurement on day 26.
  • the blood sugar was measured once again in the afternoon of the same day; an insulin solution was administered intraperitoneally (0.3unit/5 mL /kg) immediately after then; and the blood sugar was measured 30, 60, 120 and 180 minutes after insulin administration since then.
  • the insulin solution was prepared by diluting 100 unit/mL solution (Humalin R injection, Eli Lilly) with 0.1 % BSA-containing physiological saline to a concentration of 0.06unit/mL.
  • the insulin level was measured by using an insulin measurement kit (Lebis Insulin Mouse U, Shibayagi). Finally, HOMA-IR was also calculated from the values of fasting blood sugar and fasting insulin. The weight of the fat around the mouse testicles was also determined after measurement of ITT. Statistical treatment of the individual data obtained was carried out by a two-group test (unpaired t-test) or a multiplex comparison test (parametric Williams test).
  • Example 1 The compound of Example 1 exhibited a significant blood sugar-reducing effect even on DIO mice, which are known to be non-severe type-2 diabetes model mice (Table 5).
  • Examples 8 and 9 of the present invention indicate that the benzylamine derivatives represented by General Formula (I), which is represented by the compound of Example 1, are therapeutically effective not only to diabetes, but also to obesity and dyslipidemia.
  • SD male rats of 7 weeks of age were purchased and used when they are 8 weeks of age.
  • the rats were anesthetized by intraperitoneal administration of pentobarbital at 60 mg/kg; the back central region and the femoral region were cut open; a polyethylene tube (SP-31, Natsume Seisakusho Co., Ltd.) connected to a polyurethane tube (BC-3.5P, American Access Technologies) was inserted from the back to the femoral region, to place the polyethylene tube in femoral artery. After the femoral region was sutured, a flexible stainless steel pipe containing the polyethylene tube was sutured and fixed to the back skin.
  • SP-31 Polyethylene tube
  • BC-3.5P Polyurethane tube
  • Heparin at 100 IU to 200 IU/mL was filled into the polyethylene tube and the polyurethane tube for prevention of blood clotting.
  • the rats were placed and grown back in 5-compartment wire mesh cage.
  • the rats in the awake state were placed in a wire mesh cage surrounded by polystyrene foam board on the following day, a three-way cock attached to the polyurethane tube on the back was connected to a tube for measurement of blood pressure attached to a Life Kit for monitoring blood pressure (DX-360, Nihon Kohden Corp.).
  • the heart rate of the rats was determined, by sending the pulse wave obtained in the blood pressure amplifier (AP-641G, Nihon Kohden Corp.) attached to the Life Kit for monitoring blood pressure to an instantaneous heart rate meter unit (AT-601T, Nihon Kohden Corp.).
  • the heart rate was recorded on the chart paper in a thermal multirecorder (RIA-1300A, Nihon Kohden Corp.) by using a polygraph (RM-6000, Nihon Kohden Corp.).
  • physiological saline vehicle
  • physiological saline solution of the compound of Example 1 was administered in an amount of 1 mL/kg to the rats in the group with the compound of Example 1 administered.
  • the time of each administration was test-starting time.
  • the compound of Example 1 did not have any influence on rat heart rate, similarly to the vehicle ( Figure 2 ).
  • the results above indicate that there is very limited concern about the compound of Example 1 showing any adverse influence on the heart rate of cardiovascular system.
  • a male beagle and a female beagle of 11 months of age were used in the test.
  • a beagle was anesthetized by intravenous administration of thiopental sodium at 25 mg/kg, and fixed at the dorsal position under anesthesia by isoflurane inhalation with oxygen-nitrous oxide gas (1:1). Artificial respiration was carried out under the condition of 20 mL/kg and 15 times/minute.
  • bipolar extremity leads I, II and III
  • augmented unipolar extremity leads aVR, aVL and aVF
  • QT interval determined by using an electrocardiogram analyzer for animals ( ⁇ 6000AX-D, Fukuda M-E Kogyo Co., Ltd.), as needle electrodes were placed on four extremities.
  • compression electrocardiogram was printed out from the small memory card by using a long-term electrocardiogram analyzer (HS 1000 system, Fukuda M-E Kogyo Co., Ltd.).
  • the samples of the compound of Example 1 were prepared by dissolving the compound in physiological saline at concentrations of 12 mg/mL, 4 mg/mL and 1.2 mg/mL.
  • the sample was administered through a needle (22G) previously placed in the side forearm subcutaneous vein, by using an automatic injector (Harvard digital infusion pump MODEL-22, HARVARD APPAPATUS) over a period of 10 minutes.
  • an automatic injector Harmonic digital infusion pump MODEL-22, HARVARD APPAPATUS
  • vehicle physiological saline
  • 1.2 mg/mL physiological saline solution of the compound of Example 1 was administered in an amount of 0.5 mL/kg.
  • 4 mg/mL or 12 mg/mL physiological saline solution of the compound of Example 1 was administered in an amount of 0.5 mL/kg at an interval of 65 minutes after administration.
  • the QT interval and the QTc value were measured, in each administration above, 5 minutes before administration, immediately before start of administration, as well as 5, 10, 15 and 30 minutes after start of administration.
  • the measured value 30 or 60 minutes after start of previous administration corresponds to the value 5 minutes before start of administration for the following application.
  • Example 1 did not cause prolongation of the QT interval in any application and there was no arrhythmia observed in electrocardiographic waveform in any application (Table 8).
  • the new benzylamine derivatives or the pharmaceutically acceptable acid addition salts according to the present invention can be used in drugs containing it as active ingredient, in particular in therapeutic or prophylactic agents for diabetes, obesity, dyslipidemia or metabolic syndrome.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Obesity (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP09803036A 2008-07-31 2009-07-31 Therapeutic or prophylactic agent for diabetes, obesity, dyslipidemia or metabolic syndrome comprising benzylamine derivative or pharmaceutically acceptable acid addition salt thereof Not-in-force EP2311447B1 (en)

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JP2008198047 2008-07-31
PCT/JP2009/063632 WO2010013798A1 (ja) 2008-07-31 2009-07-31 ベンジルアミン誘導体又はその薬学的に許容される酸付加塩を含有する糖尿病、肥満症、脂質異常症若しくはメタボリックシンドロームの治療剤又は予防剤

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CN105403647B (zh) * 2015-10-09 2020-09-01 北京万全德众医药生物技术有限公司 一种用液相色谱法分离测定克利贝特中间体有关物质的方法

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CA2731378A1 (en) 2010-02-04
US8198330B2 (en) 2012-06-12
MX2011000844A (es) 2011-03-15
JPWO2010013798A1 (ja) 2012-01-12
CN102112122A (zh) 2011-06-29
EP2311447A1 (en) 2011-04-20
CA2731378C (en) 2013-01-29
CN102112122B (zh) 2013-04-24
EP2311447A4 (en) 2012-04-18
US20110124733A1 (en) 2011-05-26
BRPI0916641A2 (pt) 2019-10-15
JP5597992B2 (ja) 2014-10-01
ES2400118T3 (es) 2013-04-05

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